The focus of this project is the use of MRI to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by various immunomodulatory treatments and to investigate the natural history of lesions. In a relatively small cohort of patients being treated with interferon beta-1b we have observed that high neutralizing antibody (Nab) titers to interferon may affect disease activity as determined by MRI but does not seem to alter MS disease progression when compared to patients not developing Nabs. The temporal relationship between inflammation and cerebral atrophy was investigated in a longitudinal study of 19 relapsing-remitting multiple sclerosis (RRMS) patients using serial monthly contrast enhanced MRI examinations and monthly measurements of brain fractional volume (BFV) for an average of 4 years. We observed that cerebral atrophy parallels that of contrast enhancing lesion accumulation. Immunomodulatory agents that effectively reduce CEL accumulation also slow the rate of atrophy. The consistent findings in a heterogeneous group of patients treated with a variety of immunomodulatory agents, suggests that these two outcome measures may prove clinically reliable in evaluating patient response to therapy.